Adenosine is a substance that may exhibit various physiological actions when it binds to a receptor on a cell surface. The adenosine receptor on the cell surface belongs to G-protein-coupled receptor family, and it is classified into A1, A2a, A2b and A3. Among them, the adenosine A1 and adenosine A3 receptors are coupled with Gi-protein and the activation thereof results in lowering of the intracellular c-AMP level. In addition, adenosine A2a and adenosine A2b receptors are coupled with Gs-protein and the activation thereof results in heightening of the intracellular c-AMP level. These 4 kinds of adenosine receptor subtypes each have been cloned.
A variety of studies about agonists and antagonists which may work on each of the above adenosine receptor subtypes have been already reported. It has been disclosed that these agonists and antagonists could be used as medicaments for treating cardiovascular disorder, ischemic reperfusion injury, inflammation, Parkinson's disease, schizophrenia and so on. In particular, a lot of adenosine derivatives have been reported as an active compound of an adenosine A2a receptor agonist (see WO 01/027131 A1, WO 00/077018 A1, WO 00/078776 A1, WO 00/078777 A1, WO 00/078778 A1, WO 00/078779 A1, WO 00/072799 A1, WO 00/023457 A1, WO 99/67266 A1, WO 99/67265 A1, WO 99/67264 A1, WO 99/67263 A1, WO 99/41267 A1, WO 99/38877 A1, WO 98/28319 A1, U.S. Pat. No. 5,877,180, WO 00/044763 A1, WO 93/22328 A1, JP-B-1-33477, JP-B-2774169, U.S. Pat. No. 4,968,697, JP-A-63-201196, JP-A-2003-055395 and JP-A-2002-173427).
In addition, compounds which are structurally different from the above adenosine derivatives and have not any adenine structure have been also reported as an active compound of an adenosine A1 or A2 receptor agonist. The examples of the compounds include dicyanopyridine derivatives (see WO 00/125210 A1, WO 02/070484 A1, WO 02/070485 A1, WO 02/070520 A1, WO 02/079195 A1, WO 02/079196 A1, WO 03/008384 A1 and WO 03/053441 A1). However, cyanopyrimidine derivatives having an action which can activate an adenosine A2a receptor have been not known.
On the other hand, glaucoma is an intractable ophthalmopathy which most species of mammals including primates may suffer. The observed symptoms are blurred vision and ophthalmic pain or loss of vision, and field of vision may be affected through the disorder of optic nerve, in some case, leading to blindness. The glaucoma can be classified into two types: ocular hypertensive glaucoma which is characterized in an increase of intraocular pressure (a facilitation of intraocular pressure) and normal tension glaucoma without any facilitation of intraocular pressure. The facilitation of intraocular pressure in glaucoma may be induced by the loss of the balance between a flow rate of aqueous humor which is secreted from ciliary epithelium into posterior chamber and an outflow rate of aqueous humor which is excreted from anterior chamber mainly via Schlemm's canal. This loss of the balance is considered to be induced from the enhanced flow resistance of aqueous humor due to mainly blocking the outflow pathway of aqueous humor. The glaucoma is an important disease whose patients have been increasing year by year in each advanced country with the advance of aging of society, and so the social requirement regarding the development of the treatment medicament is supposed to increase more and more.
At present, in treating glaucoma, the control of the intraocular pressure which is related with the most critical factor is the most important problem, and the medicaments used in the treatment thereof include β blockers such as carteolol and timolol, prostaglandin derivatives such as latanoprost and isopropyl unoprostone, carbonic anhydrase inhibitors such as dorzolamide. These medicaments may modulate the formation or outflow of aqueous humor to lower an intraocular pressure.
The adenosine A2a receptor agonists have been reported not only to exhibit the potent antihypertensive action and to be useful as above-mentioned drugs such as an antihypertensive drug, a medicament for treating/preventing cardiac or cerebral ischemic disease and antiarteriosclerotic drug, but also to exhibit an ocular hypotensive action (see J. Pharmcol. Exp. Ther. 320-326, 273 (1995) and Eur. J. Pharmacol. 307-316, 486 (2004)).
In addition, with respect to adenosine derivatives having the intraocular pressure lowering action it has already progressed partly the research and development thereof (see JP-A-2003-055395 and JP-A-2002-173427).
However, these adenosine derivatives might be feared to accompany with some side effect for central nerve and cardiovascular system when these compounds are used as a medicament for treating glaucoma.
As mentioned above, the adenosine derivatives having the adenine structure are expected to exhibit the effect as an adenosine A2a receptor agonist, especially as a medicament for treating glaucoma and the like due to the intraocular pressure lowering action thereof, but the intraocular pressure lowering action is not enough, furthermore these compounds have a critical demerit to accompany with the side effect for central nerve and cardiovascular system, for example, the potent antihypertensive action generated from the potential adenosine A2a receptor agonistic activity arising from an adenine structure thereof. Therefore, in the related field, it is required to develop a compound that can exhibit the desired reduction of intraocular pressure as an adenosine A2a receptor agonist, especially a medicament for treating glaucoma and the like, and used more safely instead of the above compounds.